Pyrrole, Furan and Thiophene

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  • Created by: E.H13
  • Created on: 25-05-20 14:18
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  • Pyrrole, Furan and Thiophene
    • Electrophilic Aromatic Substitution
      • Strong driving force to restore aromaticity
      • Reactions are kinetically controlled in almost cases
        • Goes via the lowest energy transition state
      • Hammond Postulate
        • The TS resembles the Wheland intermediate. Stabilising the intermediate stabilises the TS.
    • Reactivity
      • 6e over 5 atoms
        • Electron rich and therefore react rapidly
      • Reaction occurs via 2 position
        • Rationalised through resonance forms; 3 vs 2
        • Reaction at the heteroatom is strongly disfavoured
        • Reaction can occur at 3/4 position if 2 and 5 positions are already substituted
      • Order of reactivity; pyrrole > furan > thiophene
        • Key factor is effectiveness of overlap of lp on heteroatom and the empty p orbital at positive centre
        • Pyrrole is both the most ThD stable and the most reactivity of the series
          • This is due to it being to having a low activiation energy due to a stabilised Wheland intermediate
        • Reactivity correlates with ability to stabilise intermediate cation
          • pKas and that
    • Pyrrole
      • Protonation
        • A weak base; pKa = -3.8
        • Occurs at all positions around the ring, but ThD most stable site is C2
        • Not beneficial to protonate N; sp3 hybridised means electrons are not delocalised and aromaticity is broken
      • Nitration
        • Extremely easy - 10^5 more reactive than benzene
        • Mild nitrating agent, e.g. acetyl nitrate
          • conc. nitric and conc. sulfuric acids decomposes pyrrole
          • Preference to 2 position, but can be altered by adding a protecting group
            • Tips - triisopropylsilyl
            • Remove using TBAF in 100%THF
      • Halogenation
        • Reactions are easy - hard to prevent over-halogenation
          • For pyrrole and furan
        • Mono bromination; NBS at low t (-25 to 0oc) in an inert solvent
          • NBS = N-bromosuccinimide
            • Mild brominating agent
    • Acylation
      • Readily undergoes Friedel-Crafts
      • 2 position is most reactive
        • Acyl chloride/ anhydride with a Lewis acid catalyst
      • No N-acylation
      • Vilsmeier reaction
        • POCl3, DMF
        • See book for mechanisms
          • Mannich Reaction
            • Formaldehyde (methanal), 2oy amine, H+
          • N can be protected using a Boc group
            • Boc2O, DMAP, acetonitrile, r.t.
      • Mannich Reaction
        • Formaldehyde (methanal), 2oy amine, H+
    • Deprotonation
      • pKa for pyrrole 17.5
        • Can be removed by strong bases
      • N can be protected using a Boc group
        • Boc2O, DMAP, acetonitrile, r.t.
    • Lithiation
      • Undergoes lithiation at position 2
        • Most electron deficient site
          • Due to inductive effects
        • Treat with alkyl lithium
        • Can be directed to 3 position by first brominating, using bulky protecting group
    • Synthetic Approaches
      • Paar-Knorr
        • Dehydration under acid condition of 1,4-dicarbonyl
      • 1,4-Dicarbonyl

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